The present invention relates to phthalazine compounds. More specifically, it relates to prophylactic and therapeutic agents for male erectile dysfunction, and prophylactic and therapeutic agents for female sexual dysfunction or dysmenorrhea.
It is said that the number of latent patients with erectile dysfunction amounts to about 3,000,000 in Japan. In U.S.A., it is reported that the number of patients with erectile dysfunction reaches 20,000,000 and 15% of males in the fifties and about ⅓ of those in the sixties suffer from this disease. In this aging society, sexual intercourse is regarded as a pleasant and emotional behavior. With the needs for the improved quality of life, it is anticipated that erectile dysfunction will raise not only a medical problem but also a social problem in future. This disease is classified into organic impotence caused by disorders in the nerves, blood vessels or muscles in the penis per se or sexual hormones and functional (psychic) impotence caused by mental or psychologic troubles. There are three factors necessary for erection, i.e., an increase in the penile arterial blood flow, the regulation of blood leakage from the penile veins, and the relaxation of the cavernous tissue. Erectile dysfunction arises when at least one of these conditions is inhibited.
The urological treatments for erectile dysfunction effected today involve drug therapy and operative penile prosthesis with the use of penile prosthetic appliances.
As the drug therapy, it is possible to inject papaverine hydrochloride or prostaglandin E1 into the penile cavernous tissue. However, this treatment is scarcely performed today, since it is not allowed in Japan that a patient gives an injection to himself and it is impossible in practice to go for a doctor every time he has coitus. In addition, the injection of papaverine hydrochloride would cause, though exceptionally, a painful symptom called priapism. Thus, the treatments with the existing drugs are not practically usable. Accordingly, it has been urgently desired to develop a drug therapy therefor which is clinically efficacious in practice.
In 1984, Bowman and Drummond reported that a selective cyclic GMP phosphodiesterase inhibitor MandB22948 (zaprinast) increased cyclic GMP in the tissue and relaxed the bovine retractor penis muscle (Cyclic GMP mediates neurogenic relaxation in the bovine retractor penis muscle, Br. J. Pharmacol., 81, 665-674, 1984). Subsequently, other workers have reported one after another the relaxation of the penis cavernosum by increasing cyclic GMP in the tissue (Int. J. Impotence Res., 4, 85-93, 1992; J. Urol., 147, 1650-1655, 1992; and N. Engl. J. Med., 326, 90-94, 1992). However, none of the compounds employed in these studies can be satisfactorily employed clinically due to poor efficacy, etc.
An inhibitor of phosphodiesterase type V is also effective against female sexual dysfunction.
Phthalazine compounds having an inhibitory action on phosphodiesterase type V are disclosed in WO9605176 (JP-A 8-225541), but there is neither disclosure on spiro compounds containing nitrogen atoms, or bicyclic and 6-memberred heterocyclic compounds thereof nor description on prevention and therapy for erectile dysfunction.
The present inventors have conducted various studies and consequently found that phthalazine compounds represented by the formula (I) show a high selectivity for phosphodiesterase type V which is an enzyme degrading cyclic GMP, and a potent inhibitory effect thereon, and exhibit a strong relaxing action on the penile cavernosum, with the increase in bioavailability and have high safety, thus completed the present invention.
The present invention relates to phthalazine compounds not specifically disclosed in JP-A 8-225541, to phthalazine compounds not suggested therein, and further to a process for producing some of the compounds.
It relates to a phthalazine compound represented by the formula (I), a pharmacologically acceptable salt thereof or a hydrate thereof: 
wherein R1 and R2 are the same as or different from each other and represent a halogen atom, a C1 to C4 alkyl group which may be substituted with a halogen atom, a hydroxyl group, a C1 to C4 alkoxy group which may be substituted with a halogen atom or a cyano group;
X represents a cyano group, a nitro group, a halogen atom, a thiocarbamoyl group, a hydroxyimino group which may be substituted with a C1 to C4 alkyl group, an aryl C1 to C4 alkyl group or a carboxy C1 to C4 alkyl group, or a heteroaryl group which may be substituted with 1 to 3 substituent groups selected from the following substituent groups A;
Y represents:
i) a group represented by the formula (II): 
xe2x80x83wherein ring A represents a 4- to 8-memberred amine ring which may be substituted with a methyl group and may have a double bond; D represents a single bond or an oxygen atom; R3 represents a hydrogen atom, a C1 to C4 alkyl group or a halogen atom; m represents an integer of 0 to 3; W represents an amino group, a hydroxyl group, a cyano group, a carboxyl group which may be protected, or a C1 to C4 alkoxy group;
ii) a group represented by the formula (III): 
xe2x80x83wherein ring B represents a 4- to 8-memberred amine ring which may have a double bond; and n and p are the same as or different from each other and represent an integer of 0 to 3;
iii) a group represented by the formula (IV): 
xe2x80x83wherein ring G represents a 4- to 8-memberred amine ring which may have a double bond, E represents a hydroxyl group, a halogen atom, a C1 to C4 alkyl group or a C1 to C4 alkoxy group, J is the formula xe2x80x94(CHR4)qxe2x80x94Q (wherein R4 represents a hydrogen atom or a C1 to C4 alkyl group, Q represents a hydroxyl group, a halogen atom, a carboxyl group which may have a protective group, a carbamoyl group or an azolyl group not containing a heteroatom other than a nitrogen atom, q is an integer of 0 or 1 to 4), or E and J may form a 3- to 6-memberred ring together with the carbon atom to which they are bound, and the ring optionally having a heteroatom and optionally having a substituent group;
iv) a group represented by the formula (V): 
xe2x80x83wherein M represents a single bond or a C1 to C4 alkylene group which may be substituted with a hydroxyl group, carboxyl group, a C1 to C4 alkyl group or a C1 to C4 alkoxy group, ring K represents a 5- to 8-memberred amine ring formed together with M, and ring L represents a 5- to 8-memberred alkyl ring which may have a substituent group and may have an oxygen atom;
v) a group represented by the formula (VI): 
xe2x80x83wherein ring P represents a 5- to 7-memberred amine ring, and R5 represents a hydrogen atom or a C1 to C4 alkyl group which may be substituted with a halogen atom, a hydroxyl group or a carboxyl group;
vi) an alkynyl group, an alkenyl group or an alkyl group all of which may have a substituent group;
vii) a phenyl group which may be substituted with 1 to 3 substituent groups selected from the following substituent group A; or
viii) a pyridyl group, a pyrimidyl group, a thienyl group, a thiazolyl group or a furyl group all of which may be substituted with 1 to 3 substituent groups selected from the following substituent group A;
xe2x80x83(substituent group A) a C1 to C4 alkyl group which may be substituted with a halogen atom, a cyano group, a nitro group or a hydroxyl group; a C1 to C4 alkoxy group which may be substituted with a halogen atom, a cyano group, a nitro group or a hydroxyl group; a cyano group; a nitro group; a carboxyl group which may have a protective group; a hydroxyl group which may have a protective group; a carbamoyl group which may be substituted with a lower alkyl group; a halogen atom; and an amino group which may be substituted with a C1 to C4 acyl group, a C1 to C4 alkylsulfonyl group or an arylsulfonyl group which may have a substituent group;
l is an integer of 1 to 3;
provided that the following cases are excluded:
the case where l is 1 or 2, X is a cyano group, a nitro group or a chlorine atom, R1 is a chlorine atom, R2 is a methoxy group, ring A is a 5- or 6-memberred amine ring, D is a single bond, m is 0, and W is a carboxyl group which may have a protective group or a C1 to C4 alkoxy group; the case where l is 1, R1 is a chlorine atom, R2 is a methoxy group, ring A is a saturated 5- or 6-memberred amine ring, D is a single bond, and W is a hydroxyl group; the case where l is 1, ring B is a 5- or 6-memberred amine ring, and both n and p are 0; the case where l is 1, E and Q are hydroxyl groups, and q is 0; and the case where l is 1, X is a chlorine atom and Y is a phenyl group substituted with a methoxy group.
Further, the present inventors have found out that compounds of the following formula (VII) also exhibit a strong relaxing action on the penile cavernosum with the increase in bioavailability, and have high safety. Thus, they have completed the present invention.
A therapeutic agent for erectile dysfunction, which comprises a phthalazine compound represented by the formula (VII), a pharmacologically acceptable salt or a hydrate thereof as an active ingredient: 
wherein lxe2x80x2 is an integer of 1 to 3; R6 represents a halogen atom, a C1 to C4 alkyl group which may be substituted with a halogen atom or a cyano group;
X1 represents a cyano group, a nitro group or a halogen atom;
Y1 represents:
i) a group represented by formula (VIII): 
xe2x80x83wherein ring A1 represents a 5- or 6-memberred amine ring; m1 is an integer of 0 or 1 to 3; and Z represents an amino group, a hydroxyl group which may have a protective group, a carboxyl group which may have a protective group, a C1 to C4 alkoxy group or a cyano group;
ii) a group represented by formula (IX): 
xe2x80x83wherein ring B1 represents a 5- or 6-memberred amine ring, n1 and p1 are integers of 0 or 1 to 3;
iii) a thiomorpholino group wherein its morpholino group or its sulfur atom may be oxidized;
iv) a phenyl group which may be substituted with 1 to 3 substituent groups selected from the following substituent group A1;
v) a heteroaryl group which is a pyridyl group, a pyrimidyl group, a thienyl group or a furyl group all of which may be substituted with 1 to 3 substituent groups selected from the following substituent group A1; or
vi) a group of formula xe2x80x94N(R7)xe2x80x94(CH2)s-Het, wherein R7 represents a lower alkyl group, Het represents a pyridyl group or a pyrimidyl group all of which may be substituted with 1 to 3 substituent groups selected from the following substituent group A1, and s is an integer of 0 or 1 to 3;
xe2x80x83(substituent group A1) a lower alkyl group substituted with a halogen atom, a cyano group, a nitro group, or a hydroxyl group, a lower alkoxy group which may be substituted with a halogen atom, cyano group, nitro group, or a hydroxyl group; a cyano group; a nitro group; a carboxyl group which may have a protective group; a hydroxyl group which may have a protective group; a carbamoyl group which may be substituted with a lower alkyl group; a halogen atom; and a phenyl group which may be substituted with an alkyl group, an alkoxy group, a halogen atom or an amino group.
The present invention provides a process for producing a compound represented by the formula (XI): 
(wherein X, Y3, R1, R2 and l have the same meanings as defined above), which comprises the step of reacting a compound represented by the formula (X): 
(wherein Hal represents a halogen atom; and R1, R2, l and X have the same meanings as defined above) with a compound of the formula Y3xe2x80x94B(OH)2 (wherein Y3 represents a phenyl group, a pyridyl group, a pyrimidyl group, a thienyl group or a furyl group all of which may have a substituent group selected from the above substituent group A1).
The present invention provides a prophylactic and therapeutic agent for erectile dysfunction, which comprises the phthalazine compound represented by the above formula (I), a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. Further, it provides a prophylactic and therapeutic agent for female sexual dysfunction or dysmenorrhea, which comprises the phthalazine compound represented by the above formula (I) or (VII), a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient.
The present invention provides a pharmaceutical composition comprising a pharmacologically or clinically effective amount of the phthalazine compound represented by the above formula (I) or (XI), a pharmacologically acceptable salt thereof or a hydrate thereof, and pharmacologically acceptable carriers.
The present invention provides a method or use for preventing or treating erectile dysfunction, female sexual dysfunction or dysmenorrhea, which comprises the step of administering a pharmacologically or clinically effective amount of the phthalazine compound represented by the above formula (I) or (VII), a pharmacologically acceptable salt thereof or a hydrate thereof to a patient suffering from erectile dysfunction, female sexual dysfunction or dysmenorrhea.
In the definitions set forth in the present invention, the halogen atoms defined in X, R1, R2, R3, R4, R5, E, Q, substituent groups A and A1 mean a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The C1 to C4 alkyl groups defined in R1, R2, R3, R4, R5, R6, R7, substituent groups A and A1 mean linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl and tert-butyl. The C1 to C4 alkoxy groups defined in R1, R2 and substituent groups A and A1 mean groups derived from the above-mentioned C1 to C4 alkyl groups, and such groups include, for example, a methoxy group, an ethoxy group, a propoxy group etc.
The protective groups in the carboxyl group which may have a protective group defined in Q, W, substituent groups A and A1 mean, for example, lower alkyl groups such as methyl group, ethyl group and tert-butyl group; lower alkyl groups substituted with a phenyl group which may have a substituent group such as p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy lower alkyl groups such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butylyloxymethyl, valelyloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy lower alkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; lower alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and 1-(isopropoxycarbonyloxy) ethyl; carboxy lower alkyl groups such as carboxymethyl and 2-carboxyethyl; heteroaryl groups such as 3-phthalidyl; benzoyloxy lower alkyl groups optionally having a substituent group such as 4-glycyloxybenzoyloxymethyl; (substituted dioxolene) lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl; cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy lower alkyl groups such as 1-cyclohexyloxycarbonyloxyethyl. In short, any group which can be degraded by any means in vivo to form a carboxylic acid can serve as a protective group for the carboxyl group.
The protective groups in the hydroxyl group which may have a protective group defined in substituent groups A and A1 mean, for example, acyl groups such as formyl group, acetyl group and benzoyl group; and lower alkoxymethyl groups such as 2-methoxyethoxymethyl group. In short, any group which can be degraded by any means in vivo to form a hydroxyl group can serve as a protective group for the hydroxyl group.
The azolyl group not containing a heteroatom other than a nitrogen atom defined in Q means groups derived from pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole and benzotriazol.
In the formula (IV), a compound produced from a ring formed by E and J together with the carbon atom to which they are bound and a ring G is a spiro compound. The ring formed by E and J together with the carbon atom to which they are bound includes cyclobutane, cyclopentane, cyclohexane, oxirane, tetrahydrofuran, tetrahydropyran, butyrolactone and butyrolactam. Further, a substituent group on these rings includes a hydroxyl group, the carboxyl group which may have the above protective group, a C1 to C4 alkyl group which may be substituted with a hydroxyl group such as a hydroxymethyl group and hydroxyethyl group, a carbonyl group and a halogen atom such as fluorine atom and chlorine atom.
In the formula (V), a bicyclo ring which, when M is a C1 to C4 alkylene group, is formed from rings K and L is meant to be a cross-linked ring. A substituent group on ring L includes a hydroxyl group, a carboxy group which may have the above protective group, a C1 to C4 alkyl group which may be substituted with a hydroxyl group such as a hydroxymethyl group and a hydroxyethyl group, a C1 to C4 alkyl group carbonyl group which may be substituted with a carboxyl group such as a carboxymethyl group and carboxyethyl group, a halogen atom such as a fluorine atom and a chlorine atom, a vinyl group, etc.
The substituent groups in the alkynyl group, alkenyl group or alkyl group wherein Y may have a substituent group include C1 to C4 alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group; groups derived from cycloalkanes such as cyclopropane, cyclobutane, cyclopentane and cyclohexane; C1 to C4 alkoxy groups derived from the above C1 to C4 alkyl groups, such as a methoxy group, ethoxy group and propoxy group etc.; a hydroxyl group; an amino group which may be substituted with a C1 to C4 alkyl group; cyclic amines which maybe substituted with a hydroxy group, for example, aziridine, azetidine, pyrrolidine and piperidine; hydroxy C1 to C4 alkyl groups; hydroxy C1 to C4 alkoxy groups; carboxyalkoxy groups; and halogen atoms such as fluorine atom and chlorine atom.
In X, the heteroaryl group includes groups derived from pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole, benzotriazole, thiazole, isothiazole, thiadiazole, benzothiadiazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline, naphthylidine, phthalazine, etc.
In the present invention, the pharmacologically acceptable salt includes, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromate and phosphate, and organic acid salts such as formate, acetate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, and toluenesulfonate.
It goes without saying that in the case of compounds having an asymmetric atom in the present invention, their optically active compounds are included within the scope of the present invention.
Further, compounds which are metabolized in vivo to form the compounds of the present invention and compounds formed through metabolism from the compounds of the present invention, are also included within the scope of the present invention.
Because of being excellent in oral absorbability and ling-lasting action, these phthalazine compounds, pharmacologically acceptable salts thereof or hydrates thereof can be percutaneously, intravenously or orally administered for treatment without resort to injection directly into the penile cavernosum or the pudenda, which makes them favorable as prophylactic and therapeutic agents for erectile dysfunction and as prophylactic and therapeutic agents for female sexual dysfunction or dysmenorrhea.
Although the administration dose of the compounds of the present invention is not particularly limited, generally, they are administered to an adult in a dose of from 5 xcexcg to 100 mg, preferably from 10 to 1,000 xcexcg, in the case of intravenous administration, or in a dose of from 1 to 1,000 mg, preferably from 5 to 100 mg, in the case of oral administration.
Production processes for producing analogous compounds of the phthalazine compounds of the present invention or pharmacologically acceptable salts thereof are described in WO9605176 (JP-A 8-225541), and the phthalazine compounds of the present invention are produced in the same manner as follows: 
wherein, Y2 is: 
wherein ring A, D, R3, m and W have the same meanings as defined above; 
wherein ring B, n and p have the same meanings as defined above; 
wherein ring G, E and J have the same meanings as defined above; 
wherein ring K, ring L and M have the same meanings as defined above; and 
wherein ring P and R5 have the same meanings as defined above;
Hal is a halogen atom; and R1, R2, l and X have the same meanings as defined above.
It is the reaction, in which the compound represented by the formula (X) is reacted with HY2 in a solvent to give the compound represented by the formula (XII). As the reaction solvent, N-methyl-2-pyrrolidine is preferable, but any solvent may be used so long as it is the one inert to the reaction. Preferable results may be obtained by using HY in excessive amount to the compound (X), or using an organic base such as diisopropyl ethylamine, or a salt such as potassium carbonate, sodium carbonate or sodium hydrogen carbonate. The reaction temperature is in the range of from room temperature to the boiling point of the solvent, preferably 100xc2x0 C. or more.
Synthesis of HY2 necessary for production of the compound wherein W is a cyano group, which is not described in WO9605176 (JP-A 8-225541), is conducted as follows: 
And, in the case where W defined above is an amino group, which is not specifically described in the above-mentioned publication, HY2 wherein an amino group is protected is synthesized and then de-protected as follows: 
In the formula (I), HY2 wherein Y is represented by the formulae (IV) and (V) can be produced by using a compound disclosed in WO9806720 or by using a process disclosed therein.
1) For example, some of the compounds represented by the formula (IV) are produced in the following process. 
wherein G1 represents a 4- to 8-memberred ring; Q1 represents a pyrrolyl, a pyrazolyl, a imidazolyl, a triazolyl, a tetrazolyl, a indazolyl, a benzimidazolyl, a benzotriazolyl group or a fluorine atom; and Pro represents a protective group for the nitrogen atom.
In a solvent such as toluene, xylene or tetrahydrofuran methyltriphenylsulfonium bromide is treated with a base such as tert-butoxide potassium or butyl lithium, and reacted with the ketone compound represented by the formula (a), whereby the compound represented by the formula (b) can be obtained. The reaction temperature is preferably xe2x88x9278xc2x0 C. to room temperature.
The compound (b) is reacted with trichloroacetyl chloride in a solvent such as diethyl ether, dimethoxyethane or tetrahydrofuran to give the dichlorocyclobutanone compound (f) (Alternatively, when it is reacted with diacetyl chloride, a monochloro-compound is obtained. The monochloro-compound can also be obtained by reacting with trichioroacetyl chloride, followed by treating with acetic acid.), and then the product is treated with a reducing agent such as zinc dust, whereby the cyclobutanone compound represented by the formula (g) can be obtained. The reaction temperature is preferably 10 to 50xc2x0 C. When the compound (g) is treated with a peroxide such as 3-chloroperbenzoic acid in the presence of sodium hydrogen carbonate in a solvent such as dichloromethane, the lactone compound represented by the formula (h) can be obtained. The reaction temperature is preferably in the range of from room temperature to 40xc2x0 C. When the compound (b) is treated with dichloroketene and diazomethane, a cyclopentanone compound in the formula (f) is obtained, and when the compound (g) is treated with diazomethane, a cyclopentanone compound in formula (g) is obtained. When the cyclopentanone compound is further treated with diazomethane, a cyclohexanone compound is obtained.
When the compound (b) is treated with a peracid such as magnesium phthalate monoperacid, the epoxide compound represented by the formula (c) is obtained. When the epoxide compound (c) is reacted with a sodium salt of azole containing nitrogen atoms only as hetero atoms in a solvent such as dimethylformamide, the corresponding compound represented by the formula (d) (Q1 is a 1-imidazolyl group, a 1-triazolyl group, etc.) is obtained. By treatment with potassium hydrogen fluoride at 100 to 150xc2x0 C. in the presence of Bu4N.H2F3, a fluoromethyl compound as the compound represented by the formula (d) wherein Q1 is a fluorine atom is obtained.
On the other hand, the fluoro compound represented by the formula (e) is obtained by treating the compound (c) is treated with hydrogen fluoride pyridine in a solvent such as methylene chloride at xe2x88x9210 to 10xc2x0 C.
2) Among the compounds represented by the formula (V), those wherein M is methylene substituted with a hydroxyl group are produced in, for example, the following process. 
The compound where ring L contains an oxygen atom can also be produced in the same manner.
Those compounds of the formula (I) wherein Y is an alkynyl group, an alkenyl group or an alkyl group all of which may have a substituent group can be produced in the following process. 
wherein Hal is a halogen atom; R8 is an optionally substituted C1 to C4 alkyl group, or an optionally substituted cycloalkyl or cycloalkylalkyl group; and R1, R2, l and X have the meanings defined above.
The reaction of the compound of the formula (X) with the alkyne compound is conducted in the presence of a catalytic amount of dichlorobistriphenyl phosphine palladium (II), cuprous iodide and a tertiary amine, at room temperature or under heating. The solvent used includes dimethylformamide or 1-methylpyrrolidinone. The tertiary amine used includes triethylamine, diisopropylethylamine, DBU and dimethylaniline. The reaction temperature is preferably 0 to 150xc2x0 C.
The conversion of the alkyne compound represented by the formula (XIII) into the alkene compound represented by the formula (XIV) or the alkane compound represented by the formula (XV) is conducted by catalytic reduction, etc. in the presence of a Lindlar catalyst or a Pd-C catalyst.
Further, the phthalazine compounds wherein Y is Y3 that is an optionally substituted aryl group or a heteroaryl group are produced as follow: 
wherein Y3 is a phenyl group, a pyridyl group, a pyrimidyl group, a thienyl group or a furyl group all of which may have 1 to 3 substituent groups selected from the above substituent group A; Hal is a halogen atom; and R1, R2, l and X have the same meanings as defined above.
The reaction is conducted by coupling the 1-halogenoquinazoline compound represented by the formula (X) by a zero-valent or divalent palladium complex to a boric acid, dialkoxy borane or trialkyl tin compound having a corresponding aryl group or heteroaryl group. The boric acid, dialkoxy borane or trialkyl tin compound having an aryl group or a heteroaryl group, and the palladium complex are dissolved or suspended in a 2-phase solvent consisting of an organic solvent and an aqueous solution of sodium carbonate. And the mixture is reacted at the temperature in the range of from at room temperature to the boiling point of the solvent for about 1 to 24 hr in a nitrogen gas stream. As the palladium complex, any palladium complex which allows the reaction to proceed can be used, and tetrakis(triphenylphosphine)palladium, etc. are preferable. As the organic solvent, any solvent which is inert to the the reaction can be used, and xylene, toluene, tetrahydrofuran or a mixed solvent thereof are preferable.
In the formula (I), the compounds shown in the following reaction scheme can be produced by combining known reactions by using the compound (XVII) wherein X is a cyano group. 
wherein R9 is a hydrogen atom, a C1 to C4 alkyl group which may be substituted with a halogen atom, an aryl C1 to C4 alkyl group or a carboxy C1 to C4 alkyl group; R10 is a C1 to C4 alkyl group; and R1, R2, l and Y have the same meanings as defined above.
Some of compounds of the formula (I) wherein X is a heteroaryl group can be produced in the same manner as in Production Process 3. 
wherein Hal is a halogen atom; Het 1 is a heteroaryl group; and R1, R2, l and Y have the same meanings as defined above.
The halogen atom is preferably a bromine atom or an iodine atom.
Further, the compounds of formula (I) with an azolyl group not having a heteroatom other than a nitrogen atom are produced according to the above-mentioned Production Process 1, after the corresponding compound represented by the formula (X) is previously produced. The corresponding compound of formula (X) is produced, for example, according to a method disclosed in WO9605176 after dimethyl 4-fluorophthalate is treated with azole not containing a heteroatom other than a nitrogen atom to give dimethyl 4-azolylphthalate and then treated with hydrazine to give 6-azolyl-2,3-dihydro-1,4-phthalazine dione.
The compound of the formula (I) wherein Y is represented by the formula (VI) can be produced by converting the compound represented by the following formula (XXIV) into the oxime in a known method: 
wherein R1, R2, R5, l and X have the same meanings as defined above.
Hereinafter, the effect of the compounds of the present invention is described by reference to Experimental Examples.
1) Inhibitory Action on the Enzyme cGMP-PDE Obtained from Porcine Platelets
The inhibitory activity of a test compound on the enzyme cGMP-PDE prepared from porcine platelets was determined by adding a solution of the test compound dissolved in DMSO to a reaction solution, where 1 xcexcM cGMP was used as the substrate in the presence of 1 mM EGTA in accordance with a method of Tompson et al. The final concentration of DMSO in the reaction solution was 1% or less. Preparation of cGMP-PDE was conducted as follows. Porcine platelets were added to buffer A (20 mM Tris/HCl, 2 mM magnesium acetate, 10 mM 2-mercaptoethanol, 0.1 mM EGTA; pH 7.4), and then sonicated. The resulting suspension was centrifuged at 100,000xc3x97g for 60 min, and the resulting supernatant was subjected to a column (DEAE-Toyopearl 650S produced by Tosoh, Tokyo, Japan). After the column was washed with buffer A, the enzyme was eluted with a gradient of from 0.075 to 0.25 M NaCl in buffer A to give a CGMP-PDE fraction. The resulting fraction was dialyzed, concentrated and stored.
2) Augmenting Action of the PDE5 Inhibitor on the Relaxing Action of Nitroprusside on a Penile Cavernosum Preparation Removed from a Rabbit
The penis was removed from a NZW white rabbit (about 3 kg) killed by intravenous administration of pentobarbital (50 mg/kg). After removal, the cavernosum was exposed by removal of surrounding tissues such as albuginea to give a preparation (about 10xc3x971.5xc3x971.5 mm). This preparation was suspended on a Magnus tube filled up with 10 ml Krebs-Henseleit""s nutritive solution (118.4 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.3 mM MgSO4, 1.2 mM KH2PO4, 25.0 mM NaHCO3, 11.0 mM glucose, 0.026 mM EDTA and 0.001 mM indomethacin) at 37xc2x0 C., and a gas mixture (95% oxygen+5% carbon dioxide) was bubbled thereinto. Then, the isometric tension was recorded under a load of 2 g. To stabilize the contraction, contraction caused by adding a potassium chloride solution (final concentration: 100 mM) and washing were repeated twice, and further, contraction by adding phenylephrine (final concentration: 10 xcexcM) and washing were also conducted.
It was filled up again with 10 ml Krebs-Henseleit""s solution, and L-NG-nitroarginine methyl ester (final concentration: 100 xcexcM) was added to inhibit the formation of endogenous nitrogen monoxide. Contraction was caused by adding phenylephrine (final concentration: 10 xcexcM), and a chemical solution was added thereto at a final concentration of 3, 30 or 300 nM. Dimethyl sulfoxide was used as the medium in this reaction. 15 min after the chemical was added, nitroprusside (final concentration: 300 xcexcM) was added to relax the preparation. Further, papaverine (final concentration: 100 xcexcM) was added to determine the maximum relaxation.
After the experiment, the tension generated upon adding papaverine was used as the base line, and the relaxation of the preparation by adding nitroprusside was recorded on a chart by using a DEGIMATIC CALIPER to determine the degree of relaxation.
Values in the table indicate relaxation ratio (%) after nitroprusside was added to the preparation pretreated with the 3, 30 and 300 nM compound, and the mean in a duplicate experiment was recorded. Further, the EC50 value indicates the compound concentration at which the contraction caused by phenylephrine is relaxed by 50%, and this value was calculated by regression analysis on a relaxation curve in the duplicate experiment.
Nitrogen monoxide formed from nitroprusside activated guanylate cyclase to promote the formation of cGMP from GTP, thus relaxing the penile cavernosum. The PDE5 inhibitor augmented this relaxation action by inhibiting the degradation of cGMP.
As described above, it was demonstrated that the compounds of the present invention have an inhibitory action on PDE5 and augment the relaxation action of nitroprusside on the rabbit penile cavernosum sample dose-dependently.
That is, the present invention is useful as a prophylactic and therapeutic agent for erectile dysfunction.